Dichloracetamido nitrophenylhydroxypropanal



United States Patent DICHLGRACETAB/HDO NITROPHENYL- HYDROXYPROPANALRobert Michel Liacob, Ablon-sur-Seine, and Jacques Georges Robert,Paris, France, assignors to Parke, Davis & Company, Detroit, Mich.

No Drawing. Application August 7, 1952, Serial No. 303,144

Claims priority, application France October 19, 1951 1 Claim. (Cl.260-562) This invention is for improvements in or relating to thepreparation of the substituted amidopropane diol,2-dichloracetamido-l-p-nitrophenylpropane 1 3-diol.

According to the present invention, the aforesaid compound is preparedby condensing p-nitrobenzaldehyde with dichloracetamidoacetaldehyde inthe presence of a basic condensing agent and reducing the substitutedpropanal thus obtained by methods known for the reduction of an aldehydeto an alcohol function without eifect upon a nitro group.

The condensation step is preferably effected in a suitable anhydrousorganic solvent such as ether at a temperature between 0 and 25 C. inthe presence of a strong organic amine e. g. a strong tertiary aminefree from hydroxyl groups, such as triethylarnine. Preferably, thereaction mixture is maintained out of contact with sunlight or othersource of actinic rays throughout the reaction.

The product of condensation is the aldol, 2-dichloracetamido-3-p-nitrophenyl-3-hydroxypropane-l-al. It is preferred directly touse for the subsequent reduction step, crude aldol having a meltingpoint between 135 and 140 C.

For the reduction step, there can be employed any method known to becapable of reducing an aldehyde to an alcohol function without affectinga nitro group. By known method is meant any method heretofore practicedor described in the chemical literature. Preferably, however, there isemployed the Meerwein method using an oxidisable aluminium alkoxide,preferably one drived from a secondary aliphatic alcohol such asaluminium isopropylate, or reduction by means of an alkali borohydride,e. g. sodium or potassium borohydride, prepared for example in themanner described in United States patent specification No. 2,461,663.This latter process is preferably efiected in an organic solvent medium,conveniently in methanol, dioxane or dimethylacetamide, at a temperaturein the neighbourhood of room temperature, for example between and 50 C.The reduction product is 2-dichloracetamido-l-p-nitrophyenylpropane 1:3-diol.

As is known, the substituted amidopropane diol prepared by the foregoingprocess is diastereoisomeric, the structural isomeric forms of which aredesignated ery- Patented June 19, 1956 thro and three respectively. TheD-threo isomer is the important anti-biotic known by the common nameChloramphenicol. The process of the present invention, which is ofconsiderable importance as a new and useful step in the synthesis ofchloramphenicol, yields a mixture containing by weight about one thirdof the DL- threo form and about two thirds of the DL-erythro form. Thismixture is separated into its useful components by methods known per se.

The present invention is illustrated by the following example:

Example 61 g. of diethyl dichloracetamidoacetal are dissolved in 61 cc.of 18% hydrochloric acid at room temperature. The solution obtained isneutralized with an aqueous sodium bicarbonate solution, and thenextracted with ether. By evaporation (under reduced pressure) of theether and of the entrained alcohol, crude dichloracetamidoacetaldehydeis obtained, which is treated with an ethereal solution of 18.9 g. ofp-nitrobenzaldehyde in 1.3 litres of ether. 50 cc. of anhydroustriethylarnine are added and the mixture is left for 2 hours indarkness, at room temperature. The gelatinous precipitate formed isfiltered and washed with a mixture of equal proportions of methanol andether. The product is dried in vacuo and 25 g. of aldol having a meltingpoint of -140 C. are obtained. This aldol is dissolved in 200 cc. ofmethanol. 4 g. of potassium borohydride are gradually added withagitation at room temperature. The solution is then taken up in 200 cc.of water and 25 cc. of 4 N caustic soda. The product is neutralized with48 cc. of 4 N sulphuric acid and extracted with ether. On evaporation ofthe ether, the resulting residue is dissolved in water. A productcrystallises, which is filtered off and dried in vacuo. 20.6 g. of aproduct melting at C. are obtained, this product being a mixture ofabout /3 of DL-threo Z-dichloracetamido-l-p-nitrophenylpropane 1:3- dioland of the corresponding DL-erythro epimer.

The diethyl dichloracetamidoacetal (B.P.o.1= l 10-120 C.)

employed as starting material is obtained by the action of methyldichloracetate on diethylaminoacetal.

We claim:

2 dichloracetamido-3-p-nitrophenyl-3-hydroxypropane l-al.

References Cited in the file of this patent UNITED STATES PATENTS

